The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation
Protein-templated fragment ligations have been established as a powerful method for the assembly and detection of optimized protein ligands. Initially developed for reversible ligations, the method has been expanded to irreversible reactions enabling the formation of super-additive fragment combinations. Here, protein-induced Mannich ligations are discovered as a biocatalytic reaction furnishing inhibitors of the transcription factor STAT5. STAT5 protein catalyzes multicomponent reactions of a phosphate mimetic, formaldehyde, and 1H-tetrazoles yielding protein ligands with greatly increased binding affinity and ligand efficiency. Reactions are induced under physiological conditions selectively by native STAT5 but not by other proteins. Formation of ligation products and (auto-)inhibition of the reaction are quantified and the mechanism is investigated. Inhibitors assembled by STAT5 block specifically the phosphorylation of this protein in a cellular model of acute myeloid leukemia (AML), DNA-binding of STAT5 dimers, expression of downstream targets of the transcription factor, and the proliferation of cancer cells in mice.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2019 |
---|---|
Erschienen: |
2019 |
Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
---|---|
Enthalten in: |
Nature communications - 10(2019), 1 vom: 08. Jan., Seite 66 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Wong, Ee Lin [VerfasserIn] |
---|
Links: |
---|
Themen: |
9007-49-2 |
---|
Anmerkungen: |
Date Completed 19.02.2019 Date Revised 09.03.2020 published: Electronic Citation Status MEDLINE |
---|
doi: |
10.1038/s41467-018-07923-2 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM292507046 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM292507046 | ||
003 | DE-627 | ||
005 | 20231225073247.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2019 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/s41467-018-07923-2 |2 doi | |
028 | 5 | 2 | |a pubmed24n0975.xml |
035 | |a (DE-627)NLM292507046 | ||
035 | |a (NLM)30622248 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Wong, Ee Lin |e verfasserin |4 aut | |
245 | 1 | 4 | |a The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation |
264 | 1 | |c 2019 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 19.02.2019 | ||
500 | |a Date Revised 09.03.2020 | ||
500 | |a published: Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Protein-templated fragment ligations have been established as a powerful method for the assembly and detection of optimized protein ligands. Initially developed for reversible ligations, the method has been expanded to irreversible reactions enabling the formation of super-additive fragment combinations. Here, protein-induced Mannich ligations are discovered as a biocatalytic reaction furnishing inhibitors of the transcription factor STAT5. STAT5 protein catalyzes multicomponent reactions of a phosphate mimetic, formaldehyde, and 1H-tetrazoles yielding protein ligands with greatly increased binding affinity and ligand efficiency. Reactions are induced under physiological conditions selectively by native STAT5 but not by other proteins. Formation of ligation products and (auto-)inhibition of the reaction are quantified and the mechanism is investigated. Inhibitors assembled by STAT5 block specifically the phosphorylation of this protein in a cellular model of acute myeloid leukemia (AML), DNA-binding of STAT5 dimers, expression of downstream targets of the transcription factor, and the proliferation of cancer cells in mice | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 7 | |a Antineoplastic Agents |2 NLM | |
650 | 7 | |a Ligands |2 NLM | |
650 | 7 | |a STAT5 Transcription Factor |2 NLM | |
650 | 7 | |a STAT5A protein, human |2 NLM | |
650 | 7 | |a STAT5B protein, human |2 NLM | |
650 | 7 | |a Tumor Suppressor Proteins |2 NLM | |
650 | 7 | |a DNA |2 NLM | |
650 | 7 | |a 9007-49-2 |2 NLM | |
700 | 1 | |a Nawrotzky, Eric |e verfasserin |4 aut | |
700 | 1 | |a Arkona, Christoph |e verfasserin |4 aut | |
700 | 1 | |a Kim, Boo Geun |e verfasserin |4 aut | |
700 | 1 | |a Beligny, Samuel |e verfasserin |4 aut | |
700 | 1 | |a Wang, Xinning |e verfasserin |4 aut | |
700 | 1 | |a Wagner, Stefan |e verfasserin |4 aut | |
700 | 1 | |a Lisurek, Michael |e verfasserin |4 aut | |
700 | 1 | |a Carstanjen, Dirk |e verfasserin |4 aut | |
700 | 1 | |a Rademann, Jörg |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Nature communications |d 2010 |g 10(2019), 1 vom: 08. Jan., Seite 66 |w (DE-627)NLM199274525 |x 2041-1723 |7 nnns |
773 | 1 | 8 | |g volume:10 |g year:2019 |g number:1 |g day:08 |g month:01 |g pages:66 |
856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41467-018-07923-2 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 10 |j 2019 |e 1 |b 08 |c 01 |h 66 |